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【结 构 式】 
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【分子编号】16245 【品名】(2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide 【CA登记号】 |
【 分 子 式 】C30H42N4O4 【 分 子 量 】522.68804 【元素组成】C 68.94% H 8.1% N 10.72% O 12.24% |
合成路线1
该中间体在本合成路线中的序号：(VIII)1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.
| 【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8. |
| 【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 . |
| 【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 . |
| 【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6. |
| 【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 | |
| (I) | 16238 | (1S,2R)-2,3-dihydro-1H-indene-1,2-diol | 67528-22-7 | C9H10O2 | 详情 | 详情 |
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (III) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (V) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (VI) | 16243 | (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO3 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (X) | 16247 | (2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one | C24H27NO2 | 详情 | 详情 | |
| (XI) | 16248 | (2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone | C24H28INO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)3) The alkylation of 5(S)-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-one (XII) by means of benzyl bromide (XIII) and lithium diisopropylamide (LDA) gives the corresponding 3(R)-benzyl derivative (XIV), which is deprotected with aqueous HF, yielding the hydroxymethyl compound (XV). The esterification of (XV) with trifluoromethanesulfonic anhydride affords the corresponding triflate (XVI), which is condensed with the chiral piperazine (VII) by means of diisopropylethylamine in isopropanol, giving the substituted furanone (XVII). Ring opening of the furanone (XVII) with LiOH, DME and imidazole yields the substituted hydroxypentanamide (XVIII), which is protected with tert-butyldimethylsilyl chloride to afford the protected amide (XIX). The trans-amidation of (XIX) with 2-hydroxyindan-1-amine (II) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in DMF gives the protected dihydroxy diamide (XX), which is deprotected with trimethylsilyl triflate, affording the dihydroxy diamide (VII), already obtained. This compound is then alkylated with 3-(chloromethyl)pyridine (IX) as before.
| 【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【2】 Vacca, J.P.; Holloway, M.K.; Dorsey, B.D.; Hungate, R.W.; Guare, J.P. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0541168; JP 1993279337; WO 9309096 . |
| 【3】 Vacca, J.P.; Guare, J.P.; Dorsey, B.D.; Holloway, M.K.; Hungate, R.W. (Merck & Co., Inc.); HIV protease inhibitors in pharmaceutical combinations for the treatment of AIDS. EP 0617968; JP 1996508496; WO 9422480 . |
| 【4】 Vacca, J.P.; Dorsey, B.D.; Guare, J.P.; Holloway, M.K.; Hungate, R.W.; Levin, R.B. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0696277; JP 1996509980; US 5413999; WO 9426717 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XII) | 16249 | (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C11H22O3Si | 详情 | 详情 | |
| (XIII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XIV) | 16251 | (3R,5S)-3-benzyl-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C18H28O3Si | 详情 | 详情 | |
| (XV) | 16252 | (3R,5S)-3-benzyl-5-(hydroxymethyl)dihydro-2(3H)-furanone | C12H14O3 | 详情 | 详情 | |
| (XVI) | 16253 | [(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl trifluoromethanesulfonate | C13H13F3O5S | 详情 | 详情 | |
| (XVII) | 16254 | tert-butyl (3S)-4-[[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | C26H39N3O5 | 详情 | 详情 | |
| (XVIII) | 16255 | tert-butyl (3S)-4-[(2S,4R)-5-amino-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | C26H42N4O5 | 详情 | 详情 | |
| (XIX) | 16256 | tert-butyl (3S)-4-((2S,4R)-5-amino-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C32H56N4O5Si | 详情 | 详情 | |
| (XX) | 16257 | tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C41H64N4O6Si | 详情 | 详情 | |
| (XXI) | 16258 | tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C35H50N4O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)4) The condensation of the chiral piperazine (VII) with (S)-(+)-glycicyl 3-nitrobenzenesulfonate (XXII) by means of diisopropylethylamine in DMF [or with (S)-glycidol (XXIII), tosyl chloride and NaH] gives the epoxide (XXIV), which is condensed with the propionamide (IV) by means of butyllithium in THF, yielding the protected hydroxyamide (XXV). The deprotection of (XXV) with aqueous HCl affords the dihydroxy-diamide (VIII), already obtained, which is finally alkylated with 3-(chloromethyl)pyridine (IX) as before.
| 【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【2】 Askin, D.; Reider, P.; Rossen, K.; Varsolona, R.J.; Wells, K.M. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502583 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XXII) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (XXIII) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (XXIV) | 16261 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]-4-[(2R)oxiranylmethyl]tetrahydro-1(2H)-pyrazinecarboxylate | C17H31N3O4 | 详情 | 详情 | |
| (XXV) | 16262 | tert-butyl (3S)-4-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C38H54N4O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Compound (I) (intermediate no. (VIII) in scheme no. 19918301a) is a key intermediate in the synthesis of indinavir. For the synthesis of the product 285239, (I) is coupled with benzofuran-2-carbaldehyde (II) via a reductive amination by means of NaBH(OAc)3 either in 1,2-dichloroethane/AcOH or in isopropyl acetate/AcOH.
| 【1】 McDaniel, S.L.; McDonough, C.; Dorsey, B.D.; et al.; Identification of MK-944a: A second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors. J Med Chem 2000, 43, 18, 3386. |
| 【3】 Lin, J.H.; Chodakewitz, J.A.; Deutsch, P.J.; Vacca, J.P.; Yeh, K.C.; Ju, W.D. (Merck & Co., Inc.); Combination therapy for the treatment of AIDS. WO 9925352 . |
| 【2】 Hoerrner, R.S.; Volante, R.P.; Purick, R.M.; Askin, D.; Reider, P.; Varsolona, R.J. (Merck & Co., Inc.); Sulfate salt of an HIV protease inhibitor having an improved oral absorption and bioavailability. EP 0986554; JP 2000513747; US 6071916; WO 9854178 . |